Chronic pain associated with the lower back is a common problem that will affect approximately two thirds of the adult population at some point in their lives (Deyo et al. 1987. Spine 12:264-268). It is the second leading reason for ambulatory care in the United States and direct medical costs are estimated at over $20 million per year (Frymoyer et al. 1991. Orthop. Clin. North Am. 22:263-271). A small but significant percentage of patients suffering from lower back pain exhibit symptoms of radicular pain associated with a herniated disk (i.e., persistent lumbar radiculopathy). Current treatment for persistent lumbar radiculopathy includes, but is not limited to, invasive surgical procedures, pharmacological therapy, and physical therapy.
Two mechanisms for production of radicular pain with or without herniated intervertebral discs have been proposed (McCarron et al. 1987. Spine 12:760-764; Olmarker, et al. 1989. J. Orthop. Res. 7:817-823; Olmarker et al. 1993. Spine 18:1425-1432; Kawakami et al. 1994. Spine 19:1780-1794). The first mechanism involves mechanical compression of the spinal root, while the second involves a biological inflammatory effect on the root induced by the herniated nucleus pulposus. However, the absence of animal models for lower back pain associated with radiculopathy has hindered the understanding of the pathophysiological mechanisms that produce radicular pain. Thus, the exact contribution of each component and elucidation of the specific role of each has not been established.
The majority of pain research using animal models has focused on injury to a peripheral nerve, in most cases the sciatic nerve. These peripheral nerve injury models in the rat reliably result in behaviors suggestive of neuropathic pain in humans (Wall et al. 1979. Pain 7:103-111; Bennett and Xie. 1988. Pain 33:87-107; Seltzer et al. 1990. Pain 43:205-218; DeLeo et al. 1991. Cryobiology. 28:460-466; DeLeo et al. 1994. Pain 56:9-16; Kim and Chung. 1992. 43:428-437). However, root lesions central to the dorsal root ganglion lead to a sequence of events that differs from lesions of peripheral nerves. Therefore, it is not possible to simply extrapolate from information gained from peripheral nerve injury in animal models and apply the findings to an understanding of the etiology of lumber radiculopathy. Therefore, animal models of lumbar radiculopathy are essential to the understanding of the etiology of lower back pain and the pathophysiology of radiculopathy.
It has been suggested that central, neuroimmune mechanisms are an important factor in the development and maintenance of chronic neuropathic pain, such as persistent lumbar radiculopathy (DeLeo et al. 1996. J. Interferon Cytokine Res. 16:695-700; DeLeo et al. 1997. Eur. J. Pain 1:115-122). Many of the events that induce hyperalgesia activate immune cells, both centrally and peripherally. Enhanced spinal neuroimmune responses have been reported in models of neuropathy, responses such as glial activation and increases in proinflammatory cytokines (Colburn et al. 1997. J. Neuroimmunol. 79:163-175; DeLeo et al. 1996. Cytokine res. 16:695-700; DeLeo et al. 1997. Brain Res. 759:5-57).
Methotrexate is a folate antagonist originally developed for treatment of malignancies and now widely used in the treatment of rheumatoid arthritis due to its potent, selective, immunosuppressive actions. Methotrexate has also been used in the treatment of psoriasis, a non-neoplastic disease of the skin characterized by rapid proliferation of epidermal cells, as well as in allogenic bone marrow and organ transplantation, treatment of dermatomyositis, Wegener's granulomatosis, and Crohn's disease (Chabner et al. 1996. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 51). As a result, the clinical safety profile of this drug has been well-established.
A new animal model for chronic pain has now been developed. Using this new model, it has now been found that methotrexate is an effective agent for the treatment of lower back pain with or without disc herniation and may be useful in the treatment of chronic neuropathic and radicular pain.